Association Between Inflammatory Skin Diseases and IgA Nephropathy

Research has shown an association between chronic kidney disease and inflammatory skin diseases (ISDs), such as atopic dermatitis (AD), acne, and psoriasis. However, research is lacking regarding a potential link between IgA nephropathy (IgAN), the predominant primary glomerular disease, and ISDs. 

To address this knowledge gap, Wenlong Cao and Jing Xiong conducted a study using bidirectional Mendelian randomization (MR) to examine causality between ISDs and IgAN. Their findings were published in Frontiers in Genetics. 

The researchers’ MR design was based on three assumptions: (1) instrumental variables (IVs) must strongly correlate with exposure; (2) IVs cannot be affected by any confounding factors; (3) IVs must relate to outcomes through exposure only and through no other causal pathway. Once those parameters were established, the researchers used bioinformatics methods to study the potential mechanism by which ISDs may cause an increased risk of IgAN. 

Exposures included AD, acne, and psoriasis, with IgAN as the outcome; conversely, IgAN was the exposure with AD, acne, and psoriasis as outcomes. All data were based on independent genome-wide association studies (GWAS). IVs of AD, acne, and psoriasis were obtained from the FinnGen Consortium and IVs of IgAN came from an available GWAS.  

An MRPRESSO test was used to detect and remove any outlier that may cause horizontal pleiotropy. A leave-one-out analysis determined whether there is an association driven by a single nucleotide polymorphism (SNP). Cochran’s Q test and funnel plot were used to evaluate heterogeneity. An MR-Egger intercept of MR-Egger was utilized to assess pleiotropy. Causal associations between exposure and outcome were presented with odds ratios and 95% confidence intervals.  

After the heterogeneity and pleiotropy tests, bidirectional causality was evaluated by an inverse variance weighted (IVW) model along with four other approaches: simple mode, weighted mode, weighted median, and MR-Egger. IVW was the primary approach, while the other four methods were supplemental. Three datasets related to AD were retrieved from the GEO database and combined. In the combined dataset, expression of galactose-deficient IgA1-associated genes were compared in atopic dermatitis patients versus healthy controls. These genes included GALNT2, GALNT12, C1GALT1, C1GALT1C1, and ST6GALNAC2. 

In a two-sample MR examining the causal effect of ISDs on IgAN, AD was associated with an increased risk of IgAN (IVW: OR, 1.054; 95% CI, 1.014–1.095; P=.0069). There was no significant association between acne or psoriasis and an increased risk of IgAN. No reverse causality was found in reverse MR between AD and IgAN (OR=1.035; 95% CI=0.873–1.227; P=.693). The IVW method indicated that IgAN may be a risk factor for psoriasis (OR=1.273; 95% CI=1.012–1.602; P=.040). However, the other four methods identified no significant association. Therefore, the evidence does not conclusively show that IgAN can increase psoriasis risk. In the combined microarray dataset, the expression levels of GALNT12 and C1GALT1C1 among patients with AD were significantly lower than in controls (P=2.3e−9; P=.00067), which may contribute to an increase in abnormal IgA1 synthesis. 

The authors acknowledge some limitations. The GWAS data used for MR were based on a European population, and results were not validated in an Asian population. Pleiotropy cannot be excluded completely. Bioinformatics methods were used to examine the potential mechanism by which AD increases the risk of IgAN. Basic research is needed to confirm the hypothesis. 

“In summary,” the authors wrote, “among ISDs, only AD was found to be a risk factor for IgAN. Potential mechanism may be linked to the aberrant expression of Gd-IgA1-related genes. Our findings may provide new insights into the pathogenesis of IgAN and innovative strategies for the prevention and treatment of IgAN.” 

Source: Frontiers in Genetics.